Photoinduced ynamide structural reshuffling and functionalization

The radical chemistry of ynamides has recently drawn the attention of synthetic organic chemists to the construction of various N-heterocyclic compounds. Nevertheless, the ynamide-radical chemistry remains a long-standing challenge for chemists due to its high reactivity, undesirable byproducts, severe inherent regio- and chemoselective problems. Importantly, the ynamide C(sp)-N bond fission remains an unsolved challenge. In this paper, we observe Photoinduced radical trigger regio- and chemoselective ynamide bond fission, structural reshuffling and functionalization of 2-alkynyl-ynamides to prepare synthetically inaccessible/challenging chalcogen-substituted indole derivatives with excellent step/atom economy. The key breakthroughs of this work includes, ynamide bond cleavage, divergent radical precursors, broad scope, easy to handle, larger-scale reactions, generation of multiple bonds (N-C(sp2), C(sp2)-C(sp2), C(sp2)-SO2R/C-SR, and C-I/C-Se/C-H) in a few minutes without photocatalysts, metals, oxidants, additives. Control experiments and 13C-labeling experiments supporting the conclusion that sulfone radicals contribute to ynamide structural reshuffling processes via a radical pathway.

of substituted 2-alkynylanilines have been reported through the utilization of transition metal/Lewis acid-catalyzed cyclization/ migration. In this strategy, an alkyne with metal (Pd, Pt, Rh, Ir, Au, Cu, Co)/Lewis acids first activated to induce the reaction, and simultaneous 1,3-migration occurs to produce straightforward indole derivatives (Fig. 1f) [37][38][39][40] . Nevertheless, despite the corresponding advances, the above process requires metal/Lewis acids and harsh reaction conditions and follows an intramolecular ionic path, no regio-or chemoselectivity issues are solved, and the reactions are restricted in terms of further functionalization of the migrating group under mild reaction conditions.
Indoles are favorable structural motifs that appear in numerous marketed drugs, the pharmaceutical industry, drug discovery, material chemistry and numerous other fields, including recent therapeutic leads [37][38][39][40][41][42][43] . Thus, the construction of inaccessible/ challenging indole ring system was a goal for altering the native indole cores, thus enabling access to chalcogen-substituted indoles as potential building blocks for drug discovery in the future. Most importantly, the available active C-I bonds in the products can be used to achieve structural modification of bioactive compounds, drugs and drug leads, as well as natural products [44][45][46] .
We considered the aforementioned challenges and our ongoing research interest in photoinduced radical cascade reactions under mild reaction conditions 47 . Photoinduced organic transformations have potential economic and operational benefits due to their efficacy, commercial availability at a low cost and complementary radical generation compared to traditional metal/ oxidants, additives and crucial requirements in chemical transformations [48][49][50][51][52][53] . We postulated that the generated chalcogen radical triggers either the alkyne or ynamide on 2-alkynylynamides to produce possible regio-and chemoselective products based on the exo/endo cyclization mode ( Fig. 1g (paths 1-4)).
In this work, we observe radical trigger regio-and chemoselective intermolecular ynamide C(sp)-N bond fission, structural reshuffling and functionalization producing synthetically inaccessible/challenging substituted indole derivatives (Fig. 1g, path 5). We are utilizing 2-alkynyl-ynamides with divergent radical precursors to prepare chalcogen-substituted indoles derivatives via the formation of multiple bonds (N-C(sp 2 ), C(sp 2 )-C(sp 2 ), C(sp 2 )-SO 2 R/C-SR, and C-I/C-Se/C-H) in a rapid transformation that occurs under mild reaction conditions with excellent step/atom economy (Fig. 1h).
Substrate scope. With the optimized standard reaction conditions in hand, we focused on the feasibility of the reaction substrate scope as depicted in Fig. 3, a broad range of substituted 2alkynyl-ynamides (1) were compatible with this transformation to produce the corresponding (E)-3-(1-iodo-2-phenyl-2-tosylvinyl)-2-phenyl-1-tosylindole 3-26 with yields ranging from 29% to 88%. Various 2-alkynyl-ynamides 1 (R = Ar) were initially screened, and the reaction produced the desired inaccessible chalcogen-substituted indole derivatives 3-9 in high yields (64-85%) in a few minutes. Long-chain aliphatic and electronwithdrawing groups in the para position smoothly tolerated the reaction and produced the desired products. Moreover, this reaction was also carried out with 2-alkynyl-ynamides 1 (R 1 = aromatic) with electron-donating groups p-Me-Ph, p-OMe-Ph, and 3,4-di-OMe-Ph, smoothly producing the desired products (10)(11)(12) in efficiently high yields without affecting the functionality. Similarly, 2-alkynyl-ynamides 1 (R 1 = aliphatic) with an n-butyl group compatible under standard reaction conditions produced the desired product (13) in good yields (74%). In addition, we were surprised to find that a highly strained cyclopropane ring was readily converted to the desired product in an excellent yield of 82%. This supports the importance of the mild reaction of our divergent radical strategy on the 2-alkynylynamides because cyclopropane is very delicate in the radical homolytic bond fission process. The molecular structure of product 14 was unambiguously confirmed by X-ray crystallography (CCDC number: 14 (2084459)). Importantly, unprotected propan-1-ol gave the desired product (15), albeit in low yield (29%) due to the freely available -OH group in the radical reaction under photoirradiation. Next, various 2-alkynylynamides 1 (R 2 = Ar) were studied, and the reactions gave the desired products in moderate to excellent yields of 35-83%. Initially, the electron-donating groups p-Me-Ph (16), p-ethyl-Ph (17), m-OMe-Ph (18) and p-OMe-Ph (19) were found to be compatible with the preparation of the desired products in excellent yields (63-83%) without affecting the substituents in the reaction transformation. To our surprise, highly substituted 3,4-5-OMe-Ph (20) produced the desired product with a moderate yield of 47%. Importantly, 2-alkynyl-ynamides 1 (R 2 = Ar) with electron-withdrawing substituents m-NO 2-Ph (21), p-COOMe-Ph (22), and p-COMe-Ph (23) were compatible with the preparation of the desired products in good yields (42-64%).
Additionally, 2,4-di-Cl-Ph (24) substitutes were also compatible for the preparation of the desired product, which was isolated with a mixture of E/Z isomers (52:48) in moderate yield (43%). The reaction with the product having naphthyl functionality (25) gave a mixture of E/Z isomers (81: 19) in moderate yield (55%). Notably, the heterocyclic moiety was smoothly converted to the desired product (26) in low yield (35%) with a mixture of E/Z isomers (76: 24), and the probable reason might be the deactivation of the alkyne in ynamide. Next, the R 2 = -CH 2 CH 2 Ph group was introduced and treated under standard reaction conditions, and the desired product (27) was obtained in moderate yield (59%). This result shows that electronic factors have no effect on the product regioselectivity and chemoselectivity in 2-alkynylynamides. Next, the scope of radical precursor reagents sulfonyl iodides/sulfonyl hydrazides (2) was tested with 2-alkynylynamides 1 to equip the corresponding inaccessible chalcogensubstituted indole derivatives 28-42 with yields ranging from 40% to 90%. Benzene sulfonyl iodide smoothly produced the desired product (28) with an excellent yield of 88%. Due to difficulties in the synthesis/isolation of sulfonyl iodides, a slight modification of the radical precursors was used for the photoinduced radical transformations (sulfonyl iodides were replaced by sulfonyl hydrazides in the presence of oxidizing agents). The reaction proceeded smoothly to give the desired product in the presence of sulfonyl halogens/sulfonyl hydrazide with a series of substituents on the aryl moiety containing electron-donating/ drawing groups, such as p-OMe-Ph (29) and p-tert-butyl (30), to give chalcogen-substituted indole derivatives in 71-82% yield. A series of aryl groups with electron-withdrawing groups, p-F-Ph (35), and p-CF 3 -Ph (36), produced the desired products in good yields of 53-78%. Our reactions were compatible with highly substituted 2,4,5-tri-Cl-Ph sulfonylhydrazine to give desired product 37 in 40% yield. In addition, a series of aliphatic functionalities (methyl (38), ethyl (39)) in compound 2 smoothly generated the desired products in good yields (54-60%). The strained cyclopropane ring was also compatible with the preparation of the corresponding product (40) in excellent yield (77%). The bulky naphthyl (41) moiety smoothly delivered the substituted indole derivatives in excellent yield (90%). Most importantly, the heterocyclic moiety (42) smoothly produced the desired product with a moderate yield of 63%. For all of the above products (except R 1 = an aliphatic group), we observe a very broad signal and no sharp peaks (in the case of R 1 = an aromatic group, a broad peak is observed at~7.8 ppm) in the 1 H NMR spectra. We hypothesized that bulky iodine could affect the neighboring aromatic protons so that the orthoprotons may broaden (Supplementary Fig. 9).
Following our previous work 47 , we treated 2-alkynyl-ynamides (1) under visible-light irradiation with thiols acting as a radical precursor (Supplementary Table 1). We focused on the feasibility of the substrate scope of the reaction, as depicted in Fig. 6. In this transformation, a series of substituted 2-alkynyl-ynamides (1) were compatible with equipping the corresponding mixture of (E/Z)-2-phenyl-3-(2-phenyl-2-(phenylthio)vinyl)-1-tosylindole derivatives in low to moderate yields with electron-donating/ withdrawing groups -Ph (76), p-Cl-Ph (77), and p-Br-Ph (78). The ratio of the E and Z mixture in the products changes with the substituents. In the case of compound 1 (R = Cl or Br), we exclusively observed the Z isomer in product 77 or the major Z isomer in product 78 (E/Z, 10:90). We believe that the radical intermediate (E) formed in the mechanism affects the formation of the single isomer ( Supplementary Fig. 54) 67 . The molecular structure of product 76 was unambiguously confirmed by X-ray crystallography (CCDC number: 76 (2084461)). Next, the reaction was also applied to 2-alkynyl-ynamides 1 (R 1 and R 2 = aromatic), where the electron-donating groups p-Me-Ph (79) and p-Me-Ph (80) produced the desired products in moderate yields of 44-50% with a mixture of E/Z ratios (47:53 and 17:83). Most importantly, various aromatic thiols containing electron-donating/electron-withdrawing groups P-Me-Ph (81), m-OMe-Ph (82), p-OMe-Ph (83), o-Br-Ph (84), and p-Br-Ph (85) produced the desired products in moderate yields of 38-53%. In all cases, we observed the formation of a mixture of E/Z isomers. According to our experimental observations, the electron-withdrawing group at R gave good selectivity (Z) compared to other substitutes, either in ynamide or thiol moieties.

Larger scale synthesis and product synthetic transformations.
To demonstrate the robustness of our diversified radical strategy (Fig. 7), we performed larger-scale reactions of 4-methyl-N-(phenylethynyl)-N-(2-(phenylethynyl)phenyl)benzenesulfonamide 1a (1.0 g of TsI (2a), 0.25 g of Se-phenyl 4-methylbenzenesulfonoselenoate (2da), and 0.25 g of benzenethiol (2ae)) that underwent smooth transformations to produce the desired products in good yields (3 (74%), 51 (60%), and 76 (46%)) without affecting the quantity of the starting material (Fig. 7a). The active C-I bond in the synthesized products was further transformed into the respective derivatives, such as p-tolylboronic acid (S26) (Suzuki reaction), producing the expected product in a good yield of 61% (86) (eq 1, Fig. 7b Fig. 6 Substrate scope of 2-alkynyl-ynamides and aromatic thiols. Reaction conditions: 2-alkynyl-ynamides 1 (0.1 mmol), aromatic thiol (0.25 mmol), and MeCN (0.1 M) were stirred at 28°C under irradiation with a 40 W Kessil blue LED for 4-7 h in air; isolated yields of the mixture of E and Z isomers were reported, and E/Z ratios were determined based on alkene protons in 1 HNMR. a Z isomer was formed. reaction conditions, the elimination of sulfone and iodine produced indole 3-substituted alkynes (87) in 58% yield (eq 2, Fig. 7b). Next, a deiodination product (88) was obtained through palladium catalysis at a moderate yield (54%) (eq 3, Fig. 7b). The products are very interesting but difficult to synthesize in the known protocols reported in the literature, and this synthetic route will be more attractive to chemists working with simple reaction conditions.

Methods
General procedure for the synthesis of (E)-3-(1-iodo/bromo-2-phenyl-2tosylvinyl)-2-phenyl-1-tosylindole derivatives (3, 5-27, 28, 30, 41, 43-47 and 98). An oven-dried screw-capped, 8 mL vial equipped with a magnetic stir bar was charged with ynamide 1 (0.10 mmol, 1.0 equiv), sulfonyl iodide/sulfonyl bromide (0.11 mmol, 1.1 equiv), and DCM (0.05 M) solvent was added. The resulting solution was stirred up to starting material completion (2-10 min) at 28°C under a blue LED light (the reaction mixture vial cooled with a fan, and the reaction mixtures were placed~8.5 cm from the blue LED light). After that, the crude reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over Na 2 SO 4 , filtered, and concentrated. The crude material was purified by flash column chromatography to give the corresponding product.
General procedure for synthesis of (E)-2-phenyl-3-(2-phenyl-1-(phenylselanyl)-2-tosylvinyl)-1-tosylindole derivatives ). An oven-dried screw-capped, 8 mL vial equipped with a magnetic stir bar was charged with ynamide (0.10 mmol, 1.0 equiv), selenosulfonates (0.11 mmol, 1.1 equiv), and DCM (0.05 M) solvent was added. The resulting solution was stirred up to starting material completion (10-30 min) at 28°C under a blue LED light (the reaction mixture vial cooled with a fan, and the reaction mixtures were placed~8.5 cm from the blue LED light). After that, the crude reaction mixture was diluted water and extracted with DCM. The organic layer was dried over Na 2 SO 4 , filtered, and concentrated. The crude material was purified by flash column chromatography to give the corresponding product.
General procedure for synthesis of (E/Z)-2-phenyl-3-(2-phenyl-2-(phenylthio)vinyl)-1-tosylindole derivatives (76-85). An oven-dried screw-capped, 8 mL vial equipped with a magnetic stir bar was charged with ynamide (0.10 mmol, 1.0 equiv) aromatic thiols (0.25 mmol, 2.5 equiv), MeCN (0.1 M) was added. The resulting solution was stirred under a blue LED light (the reaction mixture vial cooled with a fan, and the reaction mixtures were placed~8.5 cm from the blue LED light) up to starting material completion at 28°C. After that, the crude reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over Na 2 SO 4 , filtered, and concentrated. The crude material was purified by flash column chromatography to give the corresponding product.

Data availability
All data generated and analyzed during this study are included in this article and its Supplementary Information, and also available from the corresponding author. The X-ray crystallographic coordinates for structures reported in this study have been